JPS5931786A - Phosphatidyl choline-type phospholipid compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (m is 0 or 1; n is 1-10; l is 13- 21). EXAMPLE:rac-1-(p-Vinylbenzoyl)-2-stearyl-glycero-3-phosphocholine. USE:Useful for the micro-encapsulation of pharmaceuticals, enzymes, etc. It can be polymerized without using a polymerization initiator, and the polymer is free from unsatrated bond. PROCESS:The objective compound can be prepared, e.g. by (1) condensing the acid chloride of formula II with the glycerol derivative of formula III at a molar ratio of (0.5-3):1 in a solvent (e.g. anhydrous tetrahydrofuran) containing a dehydrochlorination agent (e.g. pyridine) at 0-30 deg.C for 1-20hr, (2) reacting the resultant compound of formula IV with the compound of formula V and triethylamine to obtain the compound of formula VI, and (3) treating the product with trimethylamine and silver acetate.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to phospholipid compounds, and particularly to phosphatidylcholine type phospholipid compounds having a polymerizable group.

Currently, various attempts are being made to encapsulate medicinal substances, enzymes, etc. into minute capsules and provide them as pharmaceuticals.

The early method of microencapsulation was the encapsulation of polymer compounds by emulsification method (Japanese Patent Publication No. 45-275).
7 and Japanese Patent Publication No. 50-17950) and encapsulation accompanied by the production of polymers (polyamide, etc.) by interfacial polycondensation reaction (Japanese Patent Publication No. 7395 and Japanese Patent Publication No. 1983-1983)
No. 7396). However, in these methods, for example, the toxicity of the polymer that is the encapsulating material, the toxicity due to the organic solvents (e.g. dioxane, acetone, xylene, benzene) required in the synthesis process remaining in the capsule, Sarak has a large particle size (several micrometers to 1000 micrometers) of its capsules, which tends to cause problems such as thrombosis, making it difficult to use the resulting capsules as pharmaceuticals.

By the way, the main purpose of encapsulating pharmaceutical substances and enzymes in microcapsules is to maintain the activity of pharmaceutical substances and enzymes that are unstable in vivo for a long period of time, and to maintain their effects for a long period of time.

Therefore, especially when aiming to use microcapsules as a pharmaceutical, the following conditions are particularly important, including the problems of the prior art described above. (1) Making the microcapsule particle size even smaller (several μm)
(2) improve the stability of the capsule in vivo; and (3) reduce the toxicity of the capsule material.

As a technology that satisfies these conditions to a considerable extent, various phosphorus substances, which are components of biological membranes, are formed into minute spherical aggregates (liposomes, particle size 0.05 to 10 mm) in water.
Recently, a technology to obtain microcapsules by synthesizing a phospholipid compound having a polymerizable group and polymerizing the resulting liposomes while maintaining the same state has been reported. has been done. For example, S
, IL, Journal of Regen et al.
the American Chemical
ety, 104, 791-795 (1982) (
(hereinafter referred to as document (1)), Angewanta Chemle International by H-H-Hub et al.
ionalEdit1on English version, 19,938-94
0 (1980) (hereinafter referred to as Document (II)), and Angewante Ch by A. Akimoto et al.
emleInternational Edition
See English version, 20.90-91 (1981) (hereinafter referred to as literature value).

These documents (I) to (2) describe the following polymerizable phospholipid compounds.

Reference (I) and Reference (II) 15= and 1 - Reference (1) 1 0- These synthetic phospholipid compounds form liposomes (or vehicles) in water. In order to microencapsulate this liposome in its original state, the polymerizable groups in each compound (i.e., the vinyl group in the compound of literature (1), the vinyl group in the compound of literature (1),
It is necessary to polymerize the diacetylene group in the compound of 1, and the butadiene group in the compound with literature value.

Literature (To initiate the polymerization of the compound of Therefore, when the compound of document (1) is polymerized, polymerization initiator fragments remain, which poses a problem of toxicity. Although this compound can be polymerized by ultraviolet irradiation, it requires high energy and requires very short wavelength light.

Since the compounds in Document (n) and [Phase] are polymerized by irradiation with ultraviolet rays, the problems seen in the compound in Document (1) do not occur. However, the polymerization length is large (
[) σ) Ibi, pa ≧ and of course 7"111, -CH=CH
-CH=CH- polymerization proceeds in the form -C) (-CH=CH-CH-/, etc., and many unsaturated bonds remain in the resulting capsule specific polymer. The unsaturated bond sites are difficult to metabolize in vivo. The metabolites (epoxidized vinyl groups, etc.) may be highly toxic.

Therefore, an object of the present invention is to synthesize a type of polymer that can be polymerized and microencapsulated without the need for the addition of a polymerization initiator, and in which no unsaturated bonds remain in the microcapsule polymer obtained by polymerization. An object of the present invention is to provide phospholipid compounds.

According to this invention, there is provided a phosphatidylcholine type phospholipid compound represented by the general formula %, where t is a positive integer from 13 to 21.

To produce the phospholipid compound of the present invention represented by the general formula, first, an acid chloride represented by the general formula (where m and n are as described above) is converted into an acid chloride represented by the general formula (where L is as described above). The general formula is obtained by condensation reaction with the glycerol derivative shown in c). This condensation is expressed by the formula (
B) and the compound of formula (9) molar ratio 0.5:1 to 3:1
in an appropriate solvent (e.g., tungsten, anhydrous tetrahydrofuran, chloroform, dichloromethane, etc.) containing an appropriate amount of a dehydrochlorination agent (pyridine, etc.) at 0°C to 3°C.
Perform at a temperature of 0°C. The reaction time is usually between 1 and 2 hours.
It is 0 hours.

Then, the condensation product represented by formula (c) was subjected to VanR.

Pharm, Acts H@lv by H1rt et al.
, +33.

The target compound of general formula (4) can be obtained by reacting in the following steps according to the method described in 349 (1958).

10- Condensation product (D) + Ct2-POCH'2CH2Br(
2) Amino CH3COO- Among the acid chlorides represented by the formula (B), those in which m is 0 were described as Bull by Y. Iwakura et al.

Chem, Soc, , Jap, + 4±, 18
6-191 (1968) by reacting p-carboxystyrene and thionyl chloride. In addition, when m is 1 in the acid chloride represented by the formula (B), first, Organlc 5yntheaLs+2.2
76 (1950) is obtained by improving the method described in % Formula % () (where n is as described above, R is a methyl group, an ethyl group, a propyl group, or a butyl group). Alkanedicarboxylic acid monoester e monochloride is reacted with ethylbenzene bromide in the presence of anhydrous aluminum chloride to obtain a compound represented by the formula (where n and R are as defined above). Next, this is reacted with excess alkali (eg, sodium hydroxide, potassium hydroxide) under heating in alcohol, and then acidified with hydrochloric acid or the like to obtain a compound represented by the formula. A compound represented by formula (B) can be obtained by reacting this with thionyl chloride, sioyl chloride, or the like.

A glycerol derivative beam represented by general formula (C).

By Arnold et al., Lieb, Ann, Ch.
Em, e 703 t234-239 (1967) was modified to produce 2-phenyl-5-m
- Obtained by reacting dioxykyl bromide and then hydrolyzing it with sulfuric acid in ethanol.

Note that among the glycerol derivatives represented by general formula (C), alkyl bromide, which is a raw material for synthesizing those with t of 13.15, 17.19, or 21, is convenient because it can be obtained at low cost as a commercial product. .

The phosphatidylcholine type phospholipid compound of this invention is
General methods for obtaining liposomes from natural phospholipids (e.g. Bloahimla et Biophyaia A by Papahadjopouloa et al.
eta, 13 L639-652 (j967), etc.), liposomes having an in-water particle size of 0.03 to 1 μm are formed by treating one or more of them in accordance with the method described in 13 L639-652 (j967). The ease of forming liposomes is determined by the general formula (3)
13- is larger when m is 1 than when m is 0, and the value of n is preferably larger. The column obtained in this way? By irradiating the aqueous solution of ultraviolet light or monochromatic ultraviolet light (for example, 240 nm to 310 nm), a polymerization reaction rapidly proceeds to produce microcapsules. There is no need to add any additives such as a polymerization initiator during this polymerization, and there is no need to add any additives such as a polymerization initiator.
Unlike the compounds in and (to), no unsaturated bonds remain in the polymer. The phosphatidylcholine type phospholipid compound of this invention also has low toxicity itself.

Therefore, the microcapsules obtained from the phosphatidylcholine type phospholipids of the present invention can be used to produce pharmaceuticals by encapsulating a pharmaceutical substance, enzyme, etc. therein (by polymerization in a physiologically acceptable aqueous solution containing the pharmaceutical substance, enzyme, etc.). It is useful as a reagent for various tests such as clinical tests. In addition, by encapsulating photographic photosensitizers, dyes, etc., it can also be used as a material for obtaining sharper photographs and printed images.

14- Examples of this invention will be described below.

Example 1 (A-1) J by H, Hib'bert et al.
Amer, Chem.

Soc, 62.160:1-1613 (1929) by Jun, L [eb, Ann, Che
2-
Stearyloxy-1,,3-f lonocundiol gold was synthesized.

C73,75 (73,3) However, the values in parentheses are C21T (calculated value of 4403 5 31,.9 6 26.1 20 22.7 21 14, I IR spectrum (KBr pellet) (cm-1) :33
50.2940. 2870.1470. 1120.1080, 80 (A-2) 4.55 grams (13.2 mmol) of 2-stearyloxy-1,3-pronogfudiol in 30-ml of anhydrous chloroform and 2.5 ml of dry bicarbonate.
Add f and dissolve, to which Y, Bull, Chom, Soc, + Jap-s by Iwakura et al. ↓1
, 186-191 (1968).
3.2 mmol) of anhydrous chloroform (15d) was gradually added dropwise over 30 minutes. After stirring the reaction solution at room temperature for 18 hours, it was diluted with 0.5N hydrochloric acid for 2 hours.
3 times with 50% water each, 1% sodium carbonate aqueous solution 50%
Washed once with Tnl and dehydrated with IJ sulfuric acid.

The resulting solution was filtered and the solvent was removed under reduced pressure. Transfer the residue to a silica gel column (diameter 4.5 crn, length 35
crrL) fractionation, the desired fractions were collected, the solvent was distilled off under reduced pressure, and the oily residue was dried at 50° C. using an oil pump to obtain the desired product. Yield: 3.6 grams Silica Dull Thin Layer Chromatography (TLC) (Roloform in W medium)
:Rf=0.23 (ultraviolet absorption, coloring due to engineering 2) Mass spectrum: M+=474 (molecular weight 474) 1
7- Elemental analysis value: C76,07 (75,9) Hlo, 60
(10,5) However, the values in parentheses are calculated values for C30H5004.

"C-NMR spectrum δ (ppm) value: 6
26.1 20 23.7 21 14.1 22 166.2 23 128.9 24 129.9 25 126.1 26 142.1 27 135.9 28 116.5 18- Lomoethyl) ester synthesis Von R, Hlrt et al. Pharma, Act
a Cl3F(0)CH2CH2Br synthesized according to the method described in He1v-+lU, 349 (1958)
5. O grams of anhydrous chloroform (15rn1.)
The solution was cooled with ice, and a solution of triethylamine 5-1 and 1.5 g of the monool obtained in (4) above in chloroform (101 nl) was simultaneously added dropwise from separate funnels over 2 hours. After reacting this reaction solution at room temperature for 2 hours, the progress of the reaction was confirmed by TLC. Next, this reaction solution was cooled on ice, and 200% of a 0.5N aqueous potassium chloride solution was added to it.
- was added dropwise over 1 hour. After further stirring for 1 hour, 15+d methanol was added and the chloroform layer (dark red) was separated. The target product (yellow oil) was isolated by chlorocadal column chromatography (chloroform/methanol = 10/1). Yield 1.4 grams.

19- with red coloring) 15C- was collected R spectrum δ value near ~ 19 29.7 20 22.7 21 14.1 22 165.8 23 128.8 24 130.0 25 126.1 26 142.1 27 135.9 28 116.6 2O- IR spectrum (KBr pellet Xcrn-1): 29
30.2850.1720.1610,1460°12
70.1210.1100, 1015.99o1910
．． Synthesis of 860 1.3 grams of the phosphoric acid ester compound obtained in the above (B) was dissolved in anhydrous butanone 15-, and the solution was cooled and liquefied by dragging it in a dry ice-methanol bath.
Add 5fnl and put it in a stainless steel tube and seal it.
The mixture was heated to 0.degree. C. and reacted for 10 hours with stirring. Open the tube, cool it to 0°C, and collect the resulting precipitate (product). :
It was collected by filtration, washed with acetone, and then dried. In order to remove bromide ions from this product, it was suspended in a mixed solvent of 50 parts of methanol and 5 parts of water, Ag(0OCCH5)2 Durum was added, and the mixture was reacted for 2 hours with stirring in a dark place. After filtering the reaction solution and concentrating the filtrate, silica column chromatography = 21-E (chloroform/methanol/water = 65/2515
) The desired fractions were collected and concentrated. This concentrate was dissolved in chloroform and poured into a large amount of acetone.
The precipitate was reprecipitated, centrifuged, and vacuum dried to obtain the desired phosphatidylcholine type phospholipid compound.

22- "C-NMR spectrum coverage (δ value) near ~ 19 29.7 20 22.7 21 14.1 22 166.1 23 129.1 24 129.9 25 126.0 26 142.0 27 135 .9 28 116.5 29 59.4 30 66.3 31 54.3 1210.1 to 1715.1615.1470.128
090.1060.970.920.860,820 Reference Example The phospholipid compound obtained in Example 1 was added at a concentration of 3.5×10M.
Added to water so that This was treated with ultrasonication under nitrogen (
75W at 40℃ for 5 minutes), and then left at room temperature for 1 hour, then heated with a 500W mercury lamp (UI-501C manufactured by Ushio Electric).
Light was irradiated with an optical path length of 30 cIrL. The ultraviolet absorption spectra of phospholipid compounds were measured over time.

As the reaction progressed, absorption in a characteristic absorption band (around λm□260 nm) decreased, and the absorption disappeared after about 15 minutes, confirming that the polymerization was complete. When the shape of this polymer was measured using an electron microscope (Hitachi Model H-500), it was found to be microspherical with an average particle size of 0.25 μm. When an equal volume of ethanol was added to this polymer solution, its shape did not change, indicating that the polymerized microcapsules were more stable than before polymerization. Furthermore, the thermal transition temperature of the lipid bilayer of liposomes (vehicles) before polymerization is approximately -4.5
The temperature was approximately 16.5°C after polymerization.

Example 2 Organle 5ynthes by S. Swam et al.
10.0 g (40.2 mmol) of cepacic acid monoethyl ester monochloride synthesized according to the method described in J.I.S., 2 +276 (1950),
6.2 g of bromoethylbenzene (11.2 g (83,8 mmol) of 33,5 mmol) was added. The mixture was stirred in a water bath for 4 hours and then stirred overnight at room temperature. After cooling, ice and water were added to the mixture, and then 5.7 d'i of concentrated hydrochloric acid was added slowly.To this, appropriate amounts of methylene chloride and water were added, and after shaking, the me25-ethylene chloride layer was separated. Then, methylene chloride P was added to the aqueous layer for further extraction.The methylene chloride layers were combined and dehydrated with sodium, and then methylene chloride and nitrobenzene were removed by evaporation under reduced pressure.
i diameter 4. , length 35 degrees) to obtain the desired product.

Yield: 6.6 grams (yield: 49 g).

Mass S(ctor: M+=396(C2oH2903B
Molecular weight of r1 396.398) Coloration by thymol blue) 1370.1260.1220.1180.1130,
1095.1030 Elemental analysis value: C60,20 (60,5) H7,61 (7
, 4) However, the values in parentheses are the calculated value of C2oH2903Br1 26- S5cmN dish space vector δ value: 1 33.1 2 39.0 3 143.9 4 128.4 5 128.8 6 135.8 7 199.8 8 38.5 9.14 24.9, 24.3 10-13 29.3, 29.1 15 34.3 16 173.7 17 60.1 18 14.3 27- (B)p -Synthesis of (chlorocal is nilnonanoyl)styrene CB-1) 3.3 g (83 mmol) of p-(ethoxycarvinylnonanoyl) phenylethyl bromide obtained in J.2 (4) is mixed with 40 ml of primary ethanol and powder. Added to a mixture with 6 grams of potassium hydroxide, this was heated under reflux for 2.5 hours and then cooled with water.

The produced precipitate was collected by filtration, dried, and then dissolved in 100 ml of water. Concentrated hydrochloric acid was added to this solution, and the resulting precipitate was collected and dried under reduced pressure. This product was mixed with hot toluene at 50-
and petroleum ether 150 to give the desired product (p-(hydroxycarbonylnonanoyl)styrene). Yield: 1.1 grams (yield: 46 inches).

(S') , 8H, -(CH2→T)2.31(
d,4H,-C(0)CCI(2-)2.35(t,2
H, -CI42C(0)-0-)5.49(q,2H,
-C=CH2) 29- 2860.1725.1685.1610.1470.
1440.1410.1380.1310.1245.
1190,1120゜995.980.910.840 Mass overburden torque: M+=288 (C1aHz405
Molecular weight: 288) (B-2) p-(hydroxycal is ninonanoyl) styrene obtained in (B-1): / 1.0 g (3
, 5 mmol) were added with 25 cm of dry benzene and 1 drop of dimethylformamide and stirred.

To this was added dropwise 1 m (11.8 mmol) of oxalic acid dichloride, and after stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. The residue was dried in an oil pump to obtain the desired acid chloride product, p-(chlorocarbonylnonanoyl)styrene.

30- Example 1 2-stearyloxy-1 obtained in (A-1),
To 0,995 grams (2,89 mmol) of 3-prononodiol were added 30 grams of dry methylene chloride and 0.5 grams of dry pyridine and stirred. In addition, the above (B-2)
A solution of the acid chloride obtained above (3.5 mmol) dissolved in 10-10% dry methylene chloride was slowly added dropwise over 10 minutes, and the mixture was stirred overnight. All methylene chloride was distilled off from this reaction mixture, and the residue was dissolved in chloroform. This solution was washed successively with 0.5N hydrochloric acid, water, an aqueous solution of di-sodium carbonate, and water, and then dehydrated with sodium sulfate. This was subjected to evaporation treatment under reduced pressure, and the residue was dried and purified with a silica dull column (diameter 2CrrL, length 30F) using a benzene/ether-9/1 effluent solvent to obtain the desired ether product. I got it.

3l- Rf = 0.28 (Cyclohexa Otsu 4 ethyl sulfate - 3/1
) (Ultraviolet m absorption, coloration by promthitorcar) Mass spectrum: M+-614 (molecular weight 614) Elemental analysis value: C76,38 (76,2) 810.82 (10
,7) However, the value in parentheses is the calculated value of C39H6605.
16.4 15'34.22'
135.9 16' 173.63
' 141.8 1" 14.14
' 126.2 2" 22.75
' 128.4 3" 31.96
' 136.1 17" 26.17
' 199.7 18" 7o, 58
' 38.5 9' 24.3 1690.1610.1475.1400°1370.
1295.123011185.1135.995.9
80.91o1 840.730 33- Phosphorylcholine synthesis example 1 C42P(0)OCH2CH used in (B)
2Br 3. Og was dissolved in dry chloroform 10- and cooled on ice. To this were added a solution of 1.0 g (29 mmol) of the ether product obtained in 1'1 dissolved in 10 g of dry chloroform, and a solution of 1.0 g of dry triethylamine 4-1 dissolved in 10 g of dry chloroform, respectively. They were added dropwise simultaneously from separate funnels. After stirring the reaction mixture at room temperature for 20 hours, 10 - of a 5M aqueous potassium chloride solution was slowly added dropwise, and then 10 -
Stir for hours.

After adding 10 m of methanol to this, the chloroform layer was collected, washed once with water, and evaporated to dryness.

The residue was further dried under reduced pressure over phosphorus pentoxide and then dissolved in 15 ml of dry butanone. This solution was charged into a stainless steel pressure-resistant reaction tube (for 20°C), cooled to -25°C, and then dried trimethylamine 15- was added and the tube was tightly stoppered.

This reaction mixture was reacted for 9 hours in a polyethylene glycol bath at 60°C, and the precipitate produced was collected by filtration and washed with 34-dry butanone.

The product thus obtained was dissolved directly in 70-methanol, 2.5 g of silver acetate was added, and the mixture was heated in the dark at room temperature for 1 hour.
．． Stirred for 5 hours. After filtering and draining, the filtrate was subjected to evaporation, and the residue was dried under reduced pressure, and then purified using a silica Dull column (chloroform/methanol/water - 65/25/4). In this way, the desired phosphatidylcholine type phospholipid compound was obtained.

Yield: 0.60 grams (yield: 28 grams) C-NMR spectrum (δ value): Carbon number δ (ppm) Carbon number δ (ppm)
)1.3 64.3 7' 19
9.82 77.0 8' 3
8.54 59.0 9' 2
4.46 54.4 14' 2
4.91' 116.5 15'
34.32' 135.9 16'
173.73' 141.8 1"
14.14' 126.3 2"
22,75' 128.4 3
“ 31.96' 136.1 1
7" 26.11735.1685.1615
．． 1470°1410.1360.1240.1210
．． 1095.1080.975.925, 45 Nitrogen analysis value: N1.80 (1,79) The value inside is the calculated value for C44H78N108P1.

Procedural amendment dated November 16, 1981 1, Indication of the case, Patent Application No. 140963/1982, Name of the invention: Phosphatidylcholine type phospholipid compound 3, Person making the amendment Relationship to the case Patent applicant name Sat 1) English Shun 4, Agent address: 17 Mori Building 7, 1-26-5 Toranomon, Minato-ku, Tokyo Contents of amendment (1) “2” in the second or first line from the bottom of page 18 of the specification
-stearyl” is corrected to “2-〇-stearyl”.

(2) "2-stearyl" in lines 5 to 6 on page 21 of the specification is corrected to "2-O-stearyl."

(3) “Phosphorylcholine” on line 186 of the specification
is corrected to "phosphocholine".

(4) "2-stearyl" in the first line from the bottom of page 33 of the specification is corrected to "r2-0-stearyl".

(5) "Phosphorylcholine" on page 18, line 1 of the specification is corrected to "phosphocholine."

(6) Insert r18''J directly below r17''J under "Carbon Number" in the right column of the table on page 36 of the specification.

(7) "σ (ppm)" in the right column of the table on page 36 of the specification
” below r26. Insert r70.5J directly below IJ.

(8) “Reference example” on page 824 of the specification, line 16 from the bottom
is corrected to "Reference Example 1".

(9) Insert a new line and insert the following sentence between "It was" on the 4th line of page 25 of the specification and "Example 2" on the 5th line.

"Reference Example 2 0.05M to the phospholipid compound 20+ag obtained in Example 1
- Add 10 ml of phosphate buffered water (pH 7, 0) and perform ultrasonic treatment (50 W) under a nitrogen atmosphere.

40°C for 20 minutes), and then left at 40°C for 1 hour. Using a 30W low-pressure mercury lamp (UVL-30LA manufactured by Riko Kagaku Sangyo Co., Ltd.), 50°C was heated under nitrogen at 50°C from the light source. Light was irradiated from a distance. Confirmation of polymerization was performed by diluting this liposome aqueous solution 151 in 10 ml of buffer solution (phospholipid compound concentration S: 3.84 x 1 OM) and measuring the ultraviolet absorption spectrum over time. As the reaction progressed, the absorption based on phospholipid molecules (λ%αg26Lnm) disappeared, and a new absorption at -3×251 nm was generated. A
Absorption of wqax completely disappeared after 1 hour, confirming completion of polymerization.

Note that the produced polymer was insoluble in organic solvents such as chloroform and methanol.

Reference Example 3 Sushi In order to further confirm the polymerization of the phospholipid compound in Example 1, catalytic hydrogen reduction of vinyl groups was performed in ethanol using platinum oxide as a catalyst and blowing hydrogen gas at room temperature for one hour. Comparing the ultraviolet absorption spectra of the obtained hydrogenated product, the original phospholipid compound, and the photopolymerized product, it was found that the vinyl groups in the photopolymerized product disappeared due to polymerization due to the similarity between the hydrogenated product and the photopolymerized product. It has been found. Next, the measurement results of the ultraviolet absorption spectrum are shown.

9 εw+,x
) Phospholipid ethano-27Bn+* (2xlO), 21
5n+w (0,9 hill
5!10 204n layer 1.48xlO hydrogenated ethanol 251nm
(1,43z104).

205nm 1.48xlO Photopolymerized water 251nm (1,13xlO”
) 202 nm 1.23xlOII Reference Example 4 The difficulty of polymerization by ultraviolet light irradiation was compared between the phospholipid compound of Example 1 and the diene type compound described in Document (III). Water was added to 100 mg of each and subjected to ultrasonication (50 W, 40°C for 20 minutes) to prepare a liposome aqueous solution with a concentration of 1% (w), and irradiated with light under the same conditions as in Reference Example 2. A portion of this aqueous solution was collected and diluted with water to 2.0xlOM, and the ultraviolet absorption spectrum was measured over time. The compound of literature (III) has a wavelength of 261 nm at 0
It takes 7 hours for the absorption of
In the phospholipid compound of Example 1, λwaX2.6
Disappearance of 1 nm absorption was completed within 2 hours. J(10
) Insert the following sentence in a new line after "Calculated value." on the last line of page 36 of the specification.

r Reference Example 5 It was confirmed that 20 mg of the phospholipid compound obtained in Example 2 was polymerized in the same manner as in Reference Example 2 to obtain a polymerized liposome. In addition, the produced polymer was insoluble in organic solvents such as chloroform and methanol. Example 3 According to (A-1) of Example 1, 2-phenyl-5-m-
It was synthesized by reacting dioxanol and myristyl bromide. Yield 29%. Melting point 55.5-56°C.

Elemental analysis value (wt%): H(12,58)C(70,7
8) (However, the value in parentheses is the calculated value of C1ヮH,,O,) C-NMR spectrum δ (ppm) value ('CD CI,
.

TMS) 1.3 81.9 6 28.02
79.8? -15211,3-30,04
70,21622,7 531,! 3 17 14.1 Mass spectrum: M+1 = 28!3 (molecular weight 288) (A-2) 2-Myristyloxy-1,3-P clopanediol 1
．． 0g and p-(chlorocarbonylnonanoyl)styrene synthesized in Example 2 (B) according to the method of Example 2 (C) to produce 1-(p-vinylbensoylnonamyl)glycero-myristyl ether. -2 was synthesized.

Yield 36%. Silica gel TLC: Rf = 0.17 (benzene/ether = 9/1) (ultraviolet absorption, coloration by bromothymol blue) Mass spectrum: M = 558 (molecular weight 558) Stone-NM
R (deuterochloroform, TMS): δ (ppm) 0.88 (t, 3H, -CH,); 1.26 (S wide, -(CH-); 1, [l (t, 2H, -COC
:H2-); 2.0B(t, IH, -0H)2.
32(t,2H,-C)I2COO-).

2.82 (t, 2H, KO-COCH2-); 3.5-
3.7 (m, 5H, -H(2-, -cH-);? 4, 15 (d, 2H, -CH, QC knee).

5.35, 5.82, 8.7 (d, d, q, IH, IH
,IH,-CH=CH,);7,C9(d,d,2H
,2n, -@-)"C-NMR (deuterated chloroform, T
MS): δ (ppm) 3 82.0 14° 24.91'
118.5 15' 34.22
' 135.9 18' 173.
73' 141.8 1'' 14.
14' 126.3 2" 22.
75° 128.4 3” 31.
96' 138.2 13" 2E
t, 17' 199.8 14" 7
0.68' 38.5 9' 24.4 (B) raC-1-8--vinylbenzoyl)nonanoyl-2-0-myristyl-glycero-3-phosphocholine according to the procedure (D) of Example 2, the above It was synthesized by phosphocholination of 1-(p-vinylbensoylnonanoyl)glycero-myristyl ether-2. Yield 30%.

Silica gel TLC: Rf=0.27 (chloroform/
Methanol/water = 85/25/4) (ultraviolet absorption, coloring due to bromothymol blue) Elemental analysis value (wt%): N tsgO (19,3)
(In parentheses is C4o H2ONI O1? Calculated value of PI) 13C-NMR (deuterochloroform, TMS): δ
(ppm) -2-product δ m)5- -calculation δ m4
59. 14°
24,91' 118.3 15
'34.32' 135°8
16° 173. fi3”
141.8 1″
14.14' 126.1 2"
22.85' 128.3
3"31.96'
136.1 13”
28.07' 199.8 1
4″ 70.58’ 38.5
5 86.49'
24.4 6 5
4.4 IR spectrum (chloroform solution) CIII:
2940, 2870.1730.1B80.1810.
1470°+410.1380. -1220.1180
．． 1090.975°20 Reference Example 6 It was confirmed that 20 mg of the phospholipid compound obtained in Example 3 was polymerized in the same manner as in Reference Example 2 to obtain 0 polymerized liposomes. Note that the produced polymer was insoluble in organic solvents such as chloroform and methanol. ” 1

Claims (2)

[Claims] (1) A phosphatidylcholine-type phospholipid compound represented by the general formula % (a positive integer of the formula %, and t is a positive integer of 13 to 21). (2) The phospholipidated metal article according to claim 1, wherein t is 13#15, 17.19 or 21.